Studies Aim To Improve Transplantation Response Rates In Multiple Myeloma Patients
High-dose melphalan continues to be the gold standard regimen for multiple myeloma patients prior to autologous stem cell therapy, according to a recent review of research investigating alternative preparative treatments before stem cell transplantation.
The authors of the review pointed out, however, that current research on variations of this regimen may provide improved transplantation response rates for myeloma patients in the future.
High-dose chemotherapy prior to stem cell transplantation, often called a preparative or conditioning regimen, is administered with the intention of eliminating cancerous cells from the patient’s bone marrow. High-dose chemotherapy followed by autologous stem cell transplantation is considered the standard of care for frontline treatment of newly diagnosed multiple myeloma patients under the age of 65.
High-dose melphalan (Alkeran), administered as a single dose of 200 mg/m2, is currently the most widely accepted conditioning regimen for multiple myeloma.
Recently, a number of studies have explored the possibility of altering the conditioning regimen to improve transplantation response rates.
In their article, three French myeloma specialists reviewed studies that investigated changes in melphalan dosage as well as the addition of other agents to the regimen.
Changes In Melphalan Dosing
The possibility of increasing the melphalan dose has been studied in three clinical trials. According to the authors of the review, increasing the melphalan dose to 220 mg/m2 led to encouraging results regarding the efficacy of the treatment. However, severe mouth ulcers were associated with the higher-dose treatment. The authors also pointed out that the higher 220 mg/m2 dose and the standard 200 mg/m2 dose need to be compared directly in a trial to fully understand the value of the higher dose. For more information, please see the studies in Bone Marrow Transplantation, 2003 and 1999 (abstracts), and the British Journal of Haematology (abstract).
The results of a Phase 3 trial comparing two doses of melphalan, 100 mg/m2 and 200 mg/m2,were also summarized in the review. In this study, researchers found that decreasing the melphalan dosage to 100 mg/m2 in a tandem transplant setting had no effect on overall survival, although the progression-free survival was longer in patients treated with 200 mg/m2 (see related Beacon news). The authors of the review noted that strategies to reduce the side effects of treatment need to be explored further, since the decrease of the melphalan dose by 50 percent yielded no improvement in the side effects. For more information, please see the study in the journal Blood (abstract).
Addition of Alternative Chemotherapeutic Agents
The review also summarized a recent Spanish study, in which researchers found that a conditioning regimen with oral busulfan and 200 mg/m2 melphalan increased progression-free survival following transplantation compared to melphalan alone (see related Beacon news). However, there was no difference in overall survival between the two treatments.
Furthermore, oral busulfan treatment was associated with an increased risk of death due to veno-occlusive disease, a complication of high-dose chemotherapy in which some of the small veins of the liver are blocked.
The intravenous formulation of busulfan, which other studies have demonstrated to reduce or eliminate the risk of veno-occlusive disease, may reduce the toxicity of the regimen and, according to the authors of the review, warrants further investigation. For more information, please see the full article in Haematologica.
Addition Of Radiotherapy
The use of radiotherapy as part of a conditioning regimen is also an area of active research, according to the review. Radiotherapy can be used to kill cancer cells before a stem cell transplant by using radioactive material that preferentially targets to the bone. This results in reduced side effects, especially to the liver and kidneys, compared to traditional total body irradiation.
The Phase 1/2 study of radiotherapy with an agent called holmium 166 in combination with 200 mg/m2 melphalan achieved encouraging complete response rates. However, long-term follow-up revealed the delayed onset of severe blood- and kidney-related side effects, which would exclude holmium 166 from routine clinical use. For more information, please see the study in Blood (abstract)
The results from a Phase 1 study of a radiotherapy called 153Sm-EDTMP in combination with 200 mg/m2 melphalan were much more promising, however. No delayed side effects were observed and the overall response rate was 94 percent. For more information, please see the study in Leukemia (abstract).
In the subsequent Phase 2 study, in which 153Sm-EDTMP was administered prior to 200 mg/m2 melphalan, 33 percent of patients achieved a complete response while another 26 percent achieved a very good partial response. There was, however, no difference in the overall survival or progression-free survival of patients taking 153Sm-EDTMP compared with melphalan alone. Researchers of the study concluded that further studies in the Phase 3 setting were needed. For more information, please see the American Journal of Hematology (abstract) and Leukemia (abstract).
Addition Of Novel Agents
Results from preclinical studies have suggested that treatment with melphalan in combination with Velcade (bortezomib) results in increased myeloma cell death.
Several studies have been conducted to determine what effects the addition of Velcade to a conditioning regimen has on the treatment of multiple myeloma.
Two studies were conducted in France to evaluate the response rates and tolerability of Velcade and 200 mg/m2 melphalan compared to melphalan alone as conditioning therapy in newly diagnosed patients. The complete response rate was found to be higher in the group receiving Velcade and melphalan than those receiving melphalan alone (35 percent compared to 11 percent, respectively). The addition of Velcade did not lead to an increase in blood-related side effects. For more information, please see the studies in Blood (abstract) and the Journal of Clinical Oncology (abstract).
These findings were confirmed in a similar small Phase 1/2 clinical trial conducted in the United States (see related Beacon news). The overall response rate was 87 percent, with 51 percent of patients achieving a very good partial response or better. No severe side effects were observed. For more information, please see the study in Clinical Cancer Research (abstract).
For more information, please see the review in Bone Marrow Transplantation (abstract).
Related Articles:
- Adding Clarithromycin To Velcade-Based Myeloma Treatment Regimen Fails To Increase Efficacy While Markedly Increasing Side Effects
- Nelfinavir-Velcade Combination Very Active In Advanced, Velcade-Resistant Multiple Myeloma
- Stem Cell Transplantation May Be Underutilized In Multiple Myeloma Patients In Their 80s
- Nelfinavir Shows Only Limited Success In Overcoming Revlimid Resistance In Multiple Myeloma Patients
- Sustained Complete Response To Initial Treatment Associated With Substantial Survival Benefit In Multiple Myeloma
Melissa,
Any chance you could change up the research work you are doing and try and find a vaccine for us MM patients? Based on what MM researchers appear to be studying, we really could use some fresh ideas. I cannot believe that this is what MM researchers are looking at in 2011. I understand why the Autologous Stem Cell Rescue procedure were used before the recent drugs/novel agents came into use, but I do not get why they are still commonly used when the upfront regimens now work so well. Autologous Stem Cell Rescue will never be that effective because it is based on flawed reasoning, not because Doctors are not using enough drugs. MM patients do not have Melphalan deficiencies! I wish the "Big Establishment" MM Centers would stop treating it as such. Is UAMS recommending Triple Transplants yet? More resources should be devoted to improving Allo transplants, Vaccines, or the "Killer Cells" they are just starting a Phase I clinical trial at UAMS. These are the types of Therapies we need - less drug toxicity with as good or longer remissions than the current drugs/Autologous Stem Cell Rescues that are commonly used.
I was diagnosed with MM late last year and I am very grateful for the all the great work that was done on the new drugs. I used 2 of them, Velcade and Doxil in my Induction therapy and they worked great with Dex. Researchers/Doctors/Scientists have done an outstanding job in getting drugs to market that control the disease. I view Velcade as a great accomplishment. Lets move research forward and not devote resources to 1990's ideas like Autologous Stem Cell Rescues (Single or Tandem) with Melphalan (a drug from the 50')that have shown disappointing results in Independent Clinical studies.
Marc
Marc, You're "opinion" is not shared by everyone in the MM community.
Continuing to work to improve what we have now while the bulk of the research continues to move forward is a wise course, in my opinion.
UAMS has been working on Natural Killer Cells (and it is my dear friend who will be the first HR patient to receive it) since before 2000. To use your analogy SCT wouldn't have been improved in it's administration in the last decade with all resources going to only other research? We don't even know yet if SCT won't still be used as the first line before the NK cells and it will be years of monitoring these patients before the paradigm shifts over to it exclusively. Don't get me wrong I am 100% totally hopeful this is the breakthrough we have needed, but I'm very happy that we had the options to choose our treatment course in 2008 and weren't forced to choose the path you think is best, but the one we thought was best for us. Every bit of research helps them understand better the disease and pushes it all forward. Certainly some dead ends in the journey, but you don't know until you get there. Doing SCT safer and with better results is a good thing for the thousands of patients who still choose that course of treatment.
Sure, autologous stem cell transplants have been around for a while. But they're still used for the majority of myeloma patients who are healthy enough. And not just as a rescue treatment. There's some debate about whether to have a transplant right away or after relapse, but a lot of people are doing them right away. Until transplants become obsolete, I'm happy to see some fraction of myeloma research dedicated to improving stem cell transplants, auto and allo. Of course, I'm also glad that a significant amount of research is being done on new, and hopefully even better treatments. As Lori said, we can't focus all of the research efforts on one particular thing. You can't know from the start what will work and what won't. As with financial investments, the key is diversification.
Dear Marc,
I am deeply involved in finding a novel vaccine for the prevention and treatment of hepatitis B virus, so switching my research focus at this point is unfortunately not an option.
However, you may find the following series that I wrote about new advances in myeloma vaccines interesting:
http://www.myelomabeacon.com/tag/resources-on-myeloma-vaccines/
Thank you, Melissa
Currently, just to add more to the discussion, many of these new treatment research hopes, are set up to be administered AFTER SCT, be it Auto or Allo. One that my friend is going to be involved in requires TWO Auto transplants before eligibility. SCTs, sadly, are going to be around for a bit yet, and continuing to improve on them as we move forward in researching alternatives and getting closer to a cure is one I'm grateful for. Years down the road we will probably be looking at SCT as barbaric, much like blood letting of medicine long ago. But we are not there yet. Working on the new, while improving the old (current), is a mix in research time and money that I'm very comfortable with.